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(11) | EP 0 024 122 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
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| (54) | Adenine derivatives possessing pharmacological activity |
| (57) The present invention provides the compounds of the formulae (I) and (II):
and salts thereof wherein R' is a hydrogen atom or a C1-4alkyl group; R2 is a moiety selected from hydrogen fluorine, chlorine and bromine atoms and C1-4 alkyl, C1-4 alkoxyl, C1-4 alkanoyloxy, C1-4 alkoxycarbonyl and trifluoromethyl groups; and R3 is a moiety selected from hydrogen, fluorine and chlorine atoms and Ci-4 alkyl and C1-4 alkoxyl groups, having antihyperlipidaemic activity, pharmaceutical compositions containing them and a process for their preparation. |
[0001] U.K. Patent No. 1530166 discloses that certain adenine derivatives are able to potentiate antihyperlipidaemics, inter alia 5-methylpyrazole-2-carboxylic acid. It has now been found that certain other adenine derivatives are active in their own right as antihyperlipidaemic agents.
[0002] The present invention provides the compounds of the formulae (I) and (II):
and salts thereof wherein R1 is a hydrogen atom or a C1-4 alkyl group; R2 is a moiety selected from hydrogen, fluorine, chlorine and bromine atoms and C2-4 alkyl, C1-4 alkoxyl, Cl-4 alkanoyloxy, C1-4 alkoxycarbonyl and trifluoromethyl groups; and R3 is a moiety selected from hydrogen, fluorine and chlorine atoms and C1-4 alkyl and C1-4 alkoxyl groups.
[0003] Suitable values for R1 include the hydrogen atom and the methyl, ethyl, n-propyl, iso-propyl and n-butyl groups, in particular iso-propyl.
[0004] Apt values for R2 include the hydrogen, fluorine, chlorine and bromine atoms and the methyl, methoxyl, acetoxyl, methoxycarbonyl, ethoxycarbonyl and trifluoromethyl groups.
[0008] A particularly apt value for the C6H3R2R3 moiety is the phenyl group. A further particularly apt value for the C6H3R2R3 moiety is the 2-chlorophenyl group.
[0010] It will of course be realised that the compounds of the formula (I) and (II) have a chiral centre at the -CHOH- group , and are thus capable of existing in enantiomeric forms.
[0011] The invention extends to each of the enantiomers of the compounds of the formulae (I) and (II) and to racemates thereof.
[0013] The salts of the compounds of the formulae (I) and (II) include acid addition salts and these are preferably acid addition salts with pharmaceutically acceptable acids. Such acids may be inorganic or organic acids such as hydrochloric, hydrobromic, orthophosphoric, sulphuric, methanesulphonic, acetic, citric, lactic, tartaric, propionic, benzoic and fumaric acids.
[0014] The salts of the compounds of the formulae (I) and (II) also include pharmaceutically acceptable quaternary ammonium salts. Examples of such salts include such compounds quaternised by compounds such as RS - Y wherein R5 is Cl-6 alkyl, phenyl - Cl-6 alkyl or CS-7 cycloalkyl, and Y is an anion of an acid. Suitable examples of R5 include methyl, ethyl and n- and iso-propyl; and benzyl and phenylethyl. Suitable examples of Y include the halides such as chloride, bromide and iodide.
[0016] Examples of compounds of the formula (I) include 6-amino-9-[2-hydroxy-3-(N-benzyl-N-isopropylamino)propyl]-purine and 6-amino-9-[2-hydroxy-3-(N-2'-chlorobenzylamino)-propyl]purine.
[0017] The present invention also provides a pharmaceutical composition which comprises a compound of this invention or a pharmaceutically acceptable salt thereof as hereinbefore described together with a pharmaceutically acceptable carrier.
[0018] The compositions of this invention may be adapted for administration by injection if required but it is normally preferred that they are in a form suitable for oral administration. Oral dosage forms may contain conventional excipients such as fillers, lubricants, disintegrants, binders, preservatives, colourants and so on. Suitable fillers include lactose, microcrystalline cellulose, calcium phosphate, mannitol and the like. Suitable lubricants include magnesium stearate and stearic acid. Suitable disintegrants include polyvinyl- polypyrrolidone and sodium starch glycollate.
[0019] The oral dosage forms are normally provided as discrete unit forms such as tablets and capsules. In general such unit dosage forms will contain from 5 to 500 mgs and more usually from 25 to 300 mgs of the compound of formula (I) or (II). These unit dosage forms may be administered from 1 to 6 times daily in such a way that the daily dose for a 70 kg adult will normally be between 30 to 1500 mgs and more usually from 100 to 1000 mgs, for example from 200 to 800 mgs.
[0020] In another aspect this invention provides a process for the preparation of a compound of this invention which process comprises
a. the reaction of adenine or a metal salt thereof with a compound of the formula
(III):
wherein:
Rl, R2 and R3 are as defined in formulae (I) and (II); and A is hydroxyl and Z is a group readily displaceable by
a nucleophile; or
A and Z together form an oxide diradical;
b. the reaction of a compound of the formula (IV) or (V):
wherein:
A and Z are as hereinbefore defined with a compound of the formula (VI):
wherein:
R1, R2 and R3 are as defined in formulae (I) and (II);
c. the reaction of a compound of the formula (VII) or (VIII):
wherein R1 is as hereinbefore defined, with a compound of the formula (IX):
wherein Z, R2 and R3 are as defined in formula (III);
d. the reduction of a compound of the formula (X) or (XI):
wherein R1, R2 and R32 are as defined in formulae (I) and (II);
e. for a compound of the formula (I), the reaction of formamide with a compound of
the formula (XII):
wherein R1, R2 and R3 are as defined in formulae (I) and (II); and optionally thereafter salifying the
compound of the formula (I) or (II) so produced; or converting R1 when hydrogen to a C1-4 alkyl group.
[0022] In process variants a, b and c suitable examples of Z when a group readily displaceable by a nucleophile include halogen atoms such as bromine or chlorine, and activated ester residues such as methanesulphonyloxy or toluene- sulphonyloxy.
[0023] If adenine per se is employed in process variant a then an inorganic base for example an alkali metal base such as the hydroxide or carbonate, for example potassium hydroxide or carbonate, is used to form a metal salt in situ; alternatively, a pre-formed metal salt, for example the potassium salt, is used.
[0024] The reaction of process variant a results in the preparation of a mixture of compounds of the formula (I) and (II) (c.f. J.H. Lister, "The Chemistry of Heterocyclic Compounds; Fused Pyrimidines, Part II (Purines)" (Wiley-Interscience, 1971), and this process thus also comprises the optional separation of the compounds of formulae (I) and (II) by conventional means. If both salification and separation are carried out, then they may be carried out in any appropriate order.
[0025] Separation of the compounds of the formulae (I) and (II) may be effected by fractional crystallisation or by column chromatography, for example over silica using a solvent such as chloroform or ethyl acetate optionally in the presence of a lower alkanol such as methanol.
[0026] It will be apparent that optional salification appropriately follows separation when by chromatography.
[0027] Reaction conditions of process variants b and c are substantially those for variant a. However, the presence of base is optional but preferred when Z is halogen. In variant b excess compound of formula (VI) may be used as an alternative base.
[0028] For process variant d, suitable examples of reducing agents are those which do not affect the optionally substituted benzyl group in the compounds of the formula (VI) or (VII). Such agents include borohydrides, such as sodium or lithium borohydrides, which may be used in a solvent such as diglyme, a lower alcohol or an ether, at non-extreme temperatures, such as ambient temperature.
[0029] Process variant e is suitably carried out analogously to the methods of Bredereck et al., given in Chem. Ber., 86, 333 (1953) and U.K. Patent No. 706,424.
[0030] The different enantiomeric forms of compounds of the formula (I) or (II) may be resolved by the usual methods, or any given isomer may be obtained by asymmetric synthesis, for example using a given enantiomeric form of a compound of the formula (III), (VII), (VIII) or (XII)or (IV) or (V) when A is hydroxyl.
[0031] Racemates of these compounds may be resolved conventionally, e.g. by salification with a chiral acid and separation of the resultant salts, for example as in L.F. Fieser and M. Fieser, 'Organic Chemistry', 3rd Ed., 1956, Reinhold; S.H. Wilen 'Tables of Resolving Agents and Optical-Resolutions', University of Notre Dame Press, 1972, or S.H. Wilen, 'Topics in Stereochemistry,, 1971, Vol, 6, John Wiley, NY.
[0032] The free bases of the compounds of the formulae (I) and (II) may be salified by treatment with an acid, or treatment with a compound R5Y as hereinbefore defined.
[0033] In general, within acid addition salts, di-salts are preferred, since they are more easily prepared using a slight excess of the relevant acid.
[0034] It will also be realised that salts of the compounds of the formulae (I) and (II) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of the formulae (I) and (II) or the compounds of the formulae (I) and (II) themselves, and as such form an aspect of the present invention.
[0035] The biological activity of the compounds of this invention are illustrated by the following test:
The hypocholesterolaemic and hypotriglyceridaemic effects of 6-amino-9-[2-hydroxy-3-N-benzyl-N-isopropyl-
amino)propyl]purine (Compound A) and 6-amino-9-[2-hydroxy-3-(N-o-chlorobenzylamino)propyl]purine
(Compound B) were assessed as follows. Groups of 8 male rats (Sprague-Dawley from
Tuck's) weighing 80-lOOg were given a powdered commercially available diet (Oxid)
to which compounds were added at the level of 0.1%. These diets were fed for 7 days.
The rats were then killed and the serum total cholesterol and triglyceride as well
as their high-density lipoprotein (HDL)-cholesterol were measured by a Technicon AutoAnalyser.
The results are expressed as percentage change from control values.
[0037] The following Examples illustrate the invention, and the following Descriptions illustrate the preparation of intermediates therefor:
Example 1
6-Amino-9-[2-hydroxy-3-(N-benzyl-N-isopropyl-amino)-propyl]-purine
[0038] In a 1000 ml three necked round bottomed flask, 34,6 g (0,2 mol) adenine-potassium salt are suspended in 20 ml isopropanol and the solution is refluxed. Then 0,2 moles of 1-chloro-2-hydroxy-3-(N-isopropyl-N-benzyl)aminopropane are dropped in under stirring. After 4 hours the reaction is finished. The hot reaction mixture is filtered by suction. The precipitate PO consists of potassium chloride and polar side products. The solution is cooled and the precipitate P1 is suctioned. P1 shows similar ingredients as PO. The resulting solution is treated with 25 ml ethyl acetate to precipitate the remaining side products as P2. The filtrate is evaporated to dryness and the residue recrystallised from acetonitrile. To remove polar side products, the crystals are dissolved in acetonitrile and boiled with 15 g silica gel. The hot solution is filtered and cooled and the crystalline precipitate is filtered'by suction and dried to yield the title compound (21.4g), m.p. 144°C.
Example 2
6-Amino-9-[2-hydroxy-3-(N-2'-chlorobenzyl-amino)-propyl]-purine
[0039] In a 250 ml three necked round bottomed flask, 1,38 g (0,008 mol) adenine-potassium salt are refluxed with 35 ml methanol. 1-Chloro-2-hydroxy-3-(N-o-chlorobenzyl)aminopropane is diluted with 20 ml methanol and dropped in slowly under stirring. The reaction is finished after 8 hours. The methanol is removed under reduced pressure and the residue is boiled in isopropanol and the hot solution filtered. The isopropanol solution is evaporated to dryness and the residue resolved in chloroform. This chloroform solution is filtered over 30 g silica gel, which is eluted with a chloroform/methanol mixture. The obtained pure product is recrystallised from ethylacetate to yield 300 mg, m.pt. 131°C
Description 1
1-Chloro-2-hydroxy-3-(N-isopropyl-N-benzyl)-amino-propane
[0040] 37,3 g N-isopropyl-benzylamine are diluted with 200 ml isopropanol in a 500 ml round bottomed three necked flask and 23,1 g epichlorohydrin are dropped in very slowly under stirring. The temperature is kept at 20 - 25°C. The reaction mixture is stirred over a period of 24 hours, then 1 ml epichlorohydrin is added and stirred for a further 3 hours.
Description 2
1-Chloro-2-hydroxy-3-(N-o-chlorobenzyl)-amino-propane
[0041] 1,41 g o-chlorobenzylamine are dissolved in 5 ml isopropanol in a 100 ml round bottomed three necked flask and 0,93 g epichlorohydrin are dropped in very slowly under stirring. The reaction mixture is heated to 30 - 40°C to shorten the reaction time. After 24 hours the reaction is finished. A white precipitate (~500 mg) is recombined with its mother liquor after TLC control.
and salts thereof characterised in that R1 is a hydrogen atom or a C1-4 alkyl group; R2 is a moiety selected from hydrogen, fluorine, chlorine and bromine atoms and C1-4 alkyl, C1-4 alkoxyl, C1-4 alkanoyloxy, C2-4 alkoxycarbonyl and trifluoromethyl groups; and R3 is a moiety selected from hydrogen, fluorine and chlorine atoms and C1-4 alkyl and C1-4 alkoxyl groups.
a. the reaction of adenine or a metal salt thereof with a compound of the formula
(III):
wherein: R1, R2 and R3 are as defined in claim 1 and A is hydroxyl and Z is a group readily displaceable
by a nucleophile;. or A and Z together form an oxide diradical;
b. the reaction of a compound of the formula (IV) or (V):
wherein:
A and Z are as hereinbefore defined with a compound of the formula (VI):
wherein:
R1, R2 and R3 are as defined in claim 1;
c. the reaction of a compound of the formula (VII) or (VIII):
wherein R1 is as hereinbefore defined, with a compound of the formula (IX):
wherein Z, R2 and R3 are as defined in formula (III);
d. the reduction of a compound of the formula (X) or (XI):
wherein R1, R2 and R32 are as defined in claim 1-
e. for a compound of the formula (I), the reaction of formamide with a compound of
the formula (XII):
wherein R1, R2 and R3 are as defined in claim 1 and optionally thereafter salifying the compound of the
formula (I) or (II) so produced; or converting R1 when hydrogen to a C1-4 alkyl group.
and salts thereof wherein R1 is a hydrogen atom or a C1-4 alkyl group; R2 is a moiety selected from hydrogen, fluorine, chlorine and bromine atoms and C1-4 alkyl, C1-4 alkoxyl, C1-4 alkanoyloxy, C1-4 alkoxycarbonyl and trifluoromethyl groups; and R is a moiety selected from hydrogen, fluorine and chlorine atoms and C1-4 alkyl and C1-4 alkoxyl groups, characterised by
a. the reaction of adenine or a metal salt thereof with a compound of the formula
(III):
wherein: R1, R2 and R3 are as defined in formulae (I) and (II); and A is hydroxyl and Z is a group readily
displaceable by a nucleophile; or A and Z together form an oxide diradical;
b. the reaction of a compound of the formula (IV) or (V):
wherein:
A and Z are as hereinbefore defined with a compound of the formula (VI):
wherein:
R1, R2 and R3 are as defined in formulae (I) and (II);
c. the reaction of a compound of the formula (VII) or (VIII):
wherein R1 is as hereinbefore defined, with a compound of the formula (IX):
wherein Z, R2 and R3 are as defined in formula (III);
d. the reduction of a compound of the formula (X) or (XI):
wherein R1, R2 and R32 are as defined in formulae (I) and (II);
e. for a compound of the formula (I), the reaction of formamide with a compound of
the formula (XII):
wherein R1, R2 and R3 are as defined in formulae (I) and (II); and optionally thereafter salifying the
compound of the formula (I) or (II) so produced; or converting R1 when hydrogen to a Cl-4 alkyl group.
a. the reaction of adenine or a metal salt thereof with a compound of the formula
(III):
wherein:
R1, R2 and R3 are as defined in claim 1; and A is hydroxyl and Z is a group readily displaceable by a nucleophile; or A and Z together from an oxide diradical;
b. the reaction of a compound of the formula (IV):
wherein:
A and Z are as hereinbefore defined with a compound of the formula (VI):
wherein:
R1, R2 and R3 are as defined in claim 1;
c. the reaction of a compound of the formula (VII):
wherein R1 is as hereinbefore defined, with a compound of the formula (IX):
wherein Z, R2 and R3 are as defined in formula (III);
d. the reduction of a compound of the formula (X):
wherein Rl, R2 and R32 are as defined in claim 1.
e. the reaction of formamide with a compound of the formula (XII):
wherein Rl, R2 and R3 are as defined in claim 1; and optionally thereafter salifying the compound of formula(I)
so produced; or converting R1 when hydrogen to a C1-4 alkyl group; and, for variant a, separating out the compound of the formula (I) or
salt thereof.
5. A process according to claim 4, characterised in that R1 is a hydrogen atom.